Central changes associated with chronic pelvic pain and endometriosis

“However, it is also plausible that the central changes secondary to one chronic pain condition could then predispose to the development of another (Woolf, 2011).”

“Such observations are likely to reflect plastic changes in the CNS, leading to increased sensitivity to noxious stimuli (central sensitization) (for review, see Latremoliere and Woolf (2009)).”

“There is now a significant body of literature demonstrating that chronic pain, regardless of cause, is associated with alterations in brain function, particularly with regard to the processing of pain and other sensory information (Apkarian et al., 2005; Tracey and Bushnell, 2009).”

“…is of particular concern that many of the symptoms of CPP start in adolescence or early adult life (Zondervan et al., 1999a, b; Brosens et al., 2013), a time when the CNS is very plastic (Blakemore and Choudhury, 2006; Kalia, 2008) and thus potentially more vulnerable to repeated episodes of pain.”

“Furthermore, women with fertility concerns are more likely to undergo surgical treatment of their disease (Dunselman et al., 2014), thereby increasing the potential for further damage to pelvic and endometriotic nerves.”

“Other chronic conditions have also been associated with HPA axis dysfunction, including CFS and major depression, as has post-traumatic stress disorder (Yehuda et al., 1991; Pariante and Lightman, 2008; Papadopoulos and Cleare, 2012).”

“It is of particular concern that many of the symptoms of CPP start in adolescence or early adult life (Zondervan et al., 1999a, b; Brosens et al., 2013), a time when the CNS is very plastic (Blakemore and Choudhury, 2006; Kalia, 2008) and thus potentially more vulnerable to repeated episodes of pain.”

“to increase both anxiety and pain catastrophising (an exaggerated negative response in anticipation of pain (Quartana et al., 2009)) thereby amplifying the pain experience.”

“This is common practice in other chronic pain conditions (Dworkin et al., 2010; Richards et al., 2012) but is currently poorly investigated in CPP specifically (Sator-Katzenschlager et al.”

“Burnout of the system has been proposed as one possibility (Hellhammer and Wade, 1993; Fries et al., 2005) and the recent finding that cortisol levels were negatively correlated with the duration of dysmenorrhoea (Vincent et al., 2011) would be consistent with this, suggesting that HPA axis…”

“The extent to which an individual is able to engage these mechanisms depends on a variety of factors including genetics (Mogil, 1999; Zubieta et al., 2003), psychological state and cognitive factors (Tracey and Mantyh, 2007).”

“, 2007) and IBS (Whitehead et al., 2002), whilst endometriosis is associated with a variety of autoimmune and endocrine conditions including hypothyroidism, systemic lupus erythematosus and multiple sclerosis (Sinaii et al.”

“, 1999a, b), with a significant financial cost to both the individual and society (Mathias et al., 1996), there is frequently a significant delay in diagnosis and treatment.”

“Thus anxiety amplifies pain by increasing activity within the hippocampus and entorhinal cortex (Ploghaus et al., 2001), whilst depression enhances the affective component of pain, increasing unpleasantness, and appears to disrupt activity within a network of brain regions including the amygdala and inferior frontal g…”

“Furthermore, if this symptom significantly impacts on their relationship, both self-esteem and social support may be reduced, potentially further worsening their pain experience (Culley et al., 2013).”

“…leading to neuronal atrophy or death, an effect of altered metabolic activity or neurotransmitter concentration, neurotoxic effects of drugs, neurodegeneration secondary to pain-related inactivity, and an effect related to psychological correlates such as anxiety and depression (May, 2008, 2011).”

“In view of the negative impact of chronic stress on important physiological processes including the immune system and memory function (McEwen, 2005), it has been proposed that suppression of HPA axis activity might in fact be a protective mechanism (Fries et al., 2005).”

“Activation of the HPA axis is central to the stress response (Frodl and O’Keane, 2013).”

“It is plausible that these central changes contribute to the well-established disparity between the extent of disease observed at laparoscopy and the pain experienced (Vercellini et al., 2007) and to the persistence of pain despite adequate surgical treatment.”

“However, it is important to remember that psychological dysfunction can also be a consequence of the pain (for reviews, see Blackburn-Munro and Blackburn-Munro (2001) and Blackburn-Munro (2004)).”

“There is now a significant body of literature demonstrating that chronic pain, regardless of cause, is associated with alterations in brain function, particularly with regard to the processing of pain and other sensory information (Apkarian et al., 2005; Tracey and Bushnell, 2009).”

“…direct compression/infiltration of nerves by the lesions, inflammatory pain due to the enhanced inflammatory environment of the pelvis and ‘neuropathic’ pain secondary to damage of pelvic nerves during surgery or of the new nerves directly infiltrating the lesions (Stratton and Berkley, 2011).”

“The mechanisms behind these alterations in brain volume are not completely understood but may include a direct neurotoxic effect of repeated episodes of pain leading to neuronal atrophy or death, an effect of altered metabolic activity or neurotransmitter concentration, neurotoxic effects of drugs,…”

“A recent meta-analysis of the studies investigating differences in the brain response to rectal distension between individuals with IBS and controls found differences in activation of the amygdala, thalamus, prefrontal, anterior cingulate, and insular cortices (Tillisch et al., 2011), all of which play an important ro…”

“Other chronic conditions have also been associated with HPA axis dysfunction, including CFS and major depression, as has post-traumatic stress disorder (Yehuda et al., 1991; Pariante and Lightman, 2008; Papadopoulos and Cleare, 2012).”

“In women with IBS, four studies found that dual painful stimulation decreased pain in healthy controls, while not significantly decreasing pain in patients (Wilder-Smith et al., 2004; Song et al., 2006; Wilder-Smith and Robert-Yap, 2007; Piche et al., 2010).”

“CPP can present at all ages, with studies suggesting that the prevalence increases with age (18.2/1000 in 15–20 year olds; 27.6/1000 in women over 60) (Zondervan et al., 1999a, b).”

“Interestingly, although decreases in grey matter were observed in many pain processing regions, areas with an increased volume were also observed (Schweinhardt et al., 2008; Blankstein et al., 2010; Seminowicz et al., 2010; Tu et al., 2010, 2013; As-Sanie et al., 2012).”

“, 2001), whilst depression enhances the affective component of pain, increasing unpleasantness, and appears to disrupt activity within a network of brain regions including the amygdala and inferior frontal gyrus (Berna et al., 2010).”

“Other chronic conditions have also been associated with HPA axis dysfunction, including CFS and major depression, as has post-traumatic stress disorder (Yehuda et al., 1991; Pariante and Lightman, 2008; Papadopoulos and Cleare, 2012).”

“However, these findings are not consistent, as not all studies observed an increase in all measures of the pain experience (Giamberardino et al., 1997; Bohm-Starke et al., 2001; Bajaj et al., 2002, 2003; Pukall et al., 2002; Songet al., 2006; Brinkert et al., 2007; Wilder-Smith and Robert-Yap, 2007; Sutton et al., 200…”

“Of particular interest is the recent elegantly designed study by As-Sanie and colleagues (As-Sanie et al., 2012).”

“Interestingly, although decreases in grey matter were observed in many pain processing regions, areas with an increased volume were also observed (Schweinhardt et al., 2008; Blankstein et al., 2010; Seminowicz et al., 2010; Tu et al., 2010, 2013; As-Sanie et al., 2012).”

“However, these findings are not consistent, as not all studies observed an increase in all measures of the pain experience (Giamberardino et al., 1997; Bohm-Starke et al., 2001; Bajaj et al., 2002, 2003; Pukall et al., 2002; Songet al., 2006; Brinkert et al., 2007; Wilder-Smith and Robert-Yap, 2007; Sutton et al., 200…”

“Whilst there is some evidence that this increased sensitivity may in part be reversible after successful treatment of the underlying pathology (Bajaj et al., 2003; He et al., 2010), it does not appear to be purely a reflection of the presence of ongoing pain, as women with dysmenorrhoea demonstrated enhanced behaviour…”

“However, these findings are not consistent, as not all studies observed an increase in all measures of the pain experience (Giamberardino et al., 1997; Bohm-Starke et al., 2001; Bajaj et al., 2002, 2003; Pukall et al., 2002; Songet al., 2006; Brinkert et al., 2007; Wilder-Smith and Robert-Yap, 2007; Sutton et al., 200…”

“, 2010), IC (Clauw et al., 1997; Ness et al., 2005; Powell-Boone et al., 2005) and vulvodynia/provoked vestibulodynia (Granot et al.”

“…of chronic pain states (for reviews, see Tracey and Mantyh (2007) and Tracey and Bushnell (2009)) and it has even been suggested that the inability to engage these systems may 740 Brawn et al. arch 2022 predispose to the development of chronic pain after an acute insult (De Felice et al., 2011).”

“There are a number of reasons as to why this might occur including common predisposing factors, such as genetics (Diatchenko et al., 2007) or psychological/cognitive state (for review, see Blackburn-Munro (2004)), and similar neural mechanisms (Giamberardino et al.”

“However, these findings are not consistent, as not all studies observed an increase in all measures of the pain experience (Giamberardino et al., 1997; Bohm-Starke et al., 2001; Bajaj et al., 2002, 2003; Pukall et al., 2002; Songet al., 2006; Brinkert et al., 2007; Wilder-Smith and Robert-Yap, 2007; Sutton et al., 200…”

“, 2011) and vulva (Bohm-Starke et al., 2001; Pukall et al., 2002, 2005; Giesecke et al., 2004; Lowenstein et al., 2004; Schweinhardt et al., 2008; Sutton et al., 2009; Hampson et al., 2013) but not always the back (Bajaj et al.”

“Thus, abnormally lowcortisol levels havebeen observed in women with endometriosis and CPP (Petrelluzzi et al., 2008), dysmenorrhoea (Vincent et al., 2011) and provoked vulvodynia (Ehrstrom et al., 2009) and replicated over repeated measurements (Petrelluzzi et al., 2008; Vincent et al., 2011).”

“…(Hellhammer and Wade, 1993; Fries et al., 2005) and the recent finding that cortisol levels were negatively correlated with the duration of dysmenorrhoea (Vincent et al., 2011) would be consistent with this, suggesting that HPA axis suppression is a consequence not a cause of their symptoms.”

“…the first, pressure stimulation of the vulva elicited activation of similar pain regions between women with provoked vestibulodynia and healthy controls; however, the women with provoked vestibulodynia demonstrated significantly stronger activation in several of these regions (Pukall et al., 2005).”

“…et al., 1997; Bajaj et al., 2002; Vincent et al., 2011) and vulva (Bohm-Starke et al., 2001; Pukall et al., 2002, 2005; Giesecke et al., 2004; Lowenstein et al., 2004; Schweinhardt et al., 2008; Sutton et al., 2009; Hampson et al., 2013) but not always the back (Bajaj et al., 2002, 2003).”

“…with dysmenorrhoea (Giamberardino et al., 1997; Granot et al., 2001; Bajaj et al., 2002; Vincent et al., 2011), endometriosis (Bajaj et al., 2003; Laursen et al., 2005; He et al., 2010; Neziri et al., 2010; As-Sanie et al., 2012), IBS (Wilder-Smith and Robert-Yap, 2007; Piche et al., 2010), IC…”

“Chronic fatigue syndrome (CFS) has been correlated with vulvodynia (Arnold et al., 2007) and IBS (Whitehead et al.”

“Many of the pathologies associated with CPP in women have an infective or inflammatory component (endometriosis, adenomyosis, potentially interstitial cystitis/painful bladder syndrome (IC/PBS), chronic pelvic inflammatory disease (PID), etc.), therefore a reduction in circulating glucocorticoids would be expected to…”

“Such prompt treatment, as well as being welcomed by the patient, may prevent development or progression of central changes and potentially development of other symptoms/pain conditions, in addition to improving symptoms from any other pain conditions already present (Giamberardino et al., 2010).”

“It is of particular concern that many of the symptoms of CPP start in adolescence or early adult life (Zondervan et al., 1999a, b; Brosens et al., 2013), a time when the CNS is very plastic (Blakemore and Choudhury, 2006; Kalia, 2008) and thus potentially more vulnerable to repeated episodes of pain.”

“…14 M arch 2022 have shown increased behavioural response to stimulation (both noxious and innocuous) of their bladder (Ness et al., 2005; Powell-Boone et al., 2005) and bowel (Song et al., 2006; Brinkert et al., 2007; Wilder-Smith and Robert-Yap, 2007; Elsenbruch et al., 2010; Piche et al., 2010).”

“Thus even women who only suffer with dysmenorrhoea (as opposed to pain throughout the month) have increased tendencies for depression and anxiety (Dorn et al., 2009), although this is not a universal finding (Vincent et al., 2011).”

“........................................................................................................................... Central changes associated with chronic pelvic pain and endometriosis Jennifer Brawn1,*, Matteo Morotti2,3, Krina T. Zondervan2, Christian M. Becker2, and Katy Vincent2…”

“, 2012) but is currently poorly investigated in CPP specifically (Sator-Katzenschlager et al., 2005; Horne et al., 2012).”

“It has been suggested that abnormal functioning of the ANS might responsible for some of the symptoms associated with IBS (Bockus et al., 1928).”

“In response to painful distension of the sigmoid colon and rectum, individuals with IBS have demonstrated decreases in parasympathetic and increases in sympathetic nervous system activity when compared with healthy controls (although this finding was only significant in men with IBS) (Tillisch et al., 2005).”

“As before, however, these findings are not consistent in all reported studies (see Supplementary data, Table SIII) including one study that found no differences; however, it only investigated regions within the cingulate cortex (Ringel et al., 2008).”

“…leading to neuronal atrophy or death, an effect of altered metabolic activity or neurotransmitter concentration, neurotoxic effects of drugs, neurodegeneration secondary to pain-related inactivity, and an effect related to psychological correlates such as anxiety and depression (May, 2008, 2011).”

“Burnout of the system has been proposed as one possibility (Hellhammer and Wade, 1993; Fries et al., 2005) and the recent finding that cortisol levels were negatively correlated with the duration of dysmenorrhoea (Vincent et al., 2011) would be consistent with this, suggesting that HPA axis…”

“, 2005) and vulvodynia/provoked vestibulodynia (Granot et al., 2002; Pukall et al., 2002, 2006; Giesecke et al., 2004; Foster et al., 2005; Granot, 2005; Granot and Lavee, 2005; Johannesson et al., 2007; Sutton et al., 2012; Hampson et al., 2013).”

“In healthy controls, experimentally increasing sympathetic activity has been shown to heighten visceral organ sensitivity to distension (Iovino et al., 1995).”

“…et al., 1997; Ness et al., 2005; Powell-Boone et al., 2005) and vulvodynia/provoked vestibulodynia (Granot et al., 2002; Pukall et al., 2002, 2006; Giesecke et al., 2004; Foster et al., 2005; Granot, 2005; Granot and Lavee, 2005; Johannesson et al., 2007; Sutton et al., 2012; Hampson et al., 2013).”

“…stimulation at a distant site have been demonstrated in women with CPP including in association with dysmenorrhoea (Giamberardino et al., 1997; Granot et al., 2001; Bajaj et al., 2002; Vincent et al., 2011), endometriosis (Bajaj et al., 2003; Laursen et al., 2005; He et al., 2010; Neziri et…”

“…consistent, as not all studies observed an increase in all measures of the pain experience (Giamberardino et al., 1997; Bohm-Starke et al., 2001; Bajaj et al., 2002, 2003; Pukall et al., 2002; Songet al., 2006; Brinkert et al., 2007; Wilder-Smith and Robert-Yap, 2007; Sutton et al., 2009;…”

“…of Clinical Neurosciences, University of Oxford, Oxford, UK 2Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women’s Centre, John Radcliffe Hospital, Oxford, UK 3Department of Obstetrics and Gynaecology, University of Genoa, Genoa 16100, Italy *Correspondence address.”

“…(Bajaj et al., 2003; Laursen et al., 2005; He et al., 2010; Neziri et al., 2010; As-Sanie et al., 2012), IBS (Wilder-Smith and Robert-Yap, 2007; Piche et al., 2010), IC (Clauw et al., 1997; Ness et al., 2005; Powell-Boone et al., 2005) and vulvodynia/provoked vestibulodynia (Granot et al.,…”

“However, it should be stated that this is not a systematic review.”

“However, it is important to remember that psychological dysfunction can also be a consequence of the pain (for reviews, see Blackburn-Munro and Blackburn-Munro (2001) and Blackburn-Munro (2004)).”

“Perhaps not surprisingly, the first of these (Tu et al., 2009), showed that brain metabolism Central changes in pelvic pain conditions 739”

“…et al., 1997; Ness et al., 2005; Powell-Boone et al., 2005) and vulvodynia/provoked vestibulodynia (Granot et al., 2002; Pukall et al., 2002, 2006; Giesecke et al., 2004; Foster et al., 2005; Granot, 2005; Granot and Lavee, 2005; Johannesson et al., 2007; Sutton et al., 2012; Hampson et al., 2013).”

“Interestingly, although decreases in grey matter were observed in many pain processing regions, areas with an increased volume were also observed (Schweinhardt et al., 2008; Blankstein et al., 2010; Seminowicz et al., 2010; Tu et al., 2010, 2013; As-Sanie et al., 2012).”

“It has been suggested that abnormal functioning of the ANS might responsible for some of the symptoms associated with IBS (Bockus et al., 1928).”

“Similarly, women with endometriosis (Sepulcri Rde and do Amaral, 2009; Smorgick et al., 2013) and provoked vestibulodynia (Nunns and Mandal, 1997) are more likely to have anxiety or depression, but may otherwise be psychologically healthy (Eriksen et al.”

“This is common practice in other chronic pain conditions (Dworkin et al., 2010; Richards et al., 2012) but is currently poorly investigated in CPP specifically (Sator-Katzenschlager et al.”

“Whilst there is some evidence that this increased sensitivity may in part be reversible after successful treatment of the underlying pathology (Bajaj et al., 2003; He et al., 2010), it does not appear to be purely a reflection of the presence of ongoing pain, as women with dysmenorrhoea demonstrated enhanced behaviour…”

“, 2011) and vulva (Bohm-Starke et al., 2001; Pukall et al., 2002, 2005; Giesecke et al., 2004; Lowenstein et al., 2004; Schweinhardt et al., 2008; Sutton et al., 2009; Hampson et al., 2013) but not always the back (Bajaj et al.”

“Similarly, women with endometriosis (Sepulcri Rde and do Amaral, 2009; Smorgick et al., 2013) and provoked vestibulodynia (Nunns and Mandal, 1997) are more likely to have anxiety or depression, but may otherwise be psychologically healthy (Eriksen et al., 2008).”

“…that chronicpain can be consideredas a repeated stressor, both physiologically and psychologically, it is probably not surprising that dysfunction in the activity of the HPA axis is an almost universal finding in chronic pain conditions (Griep et al., 1998; Gaab et al., 2005; Galli et al., 2009).”

“However, these findings are not consistent, as not all studies observed an increase in all measures of the pain experience (Giamberardino et al., 1997; Bohm-Starke et al., 2001; Bajaj et al., 2002, 2003; Pukall et al., 2002; Songet al., 2006; Brinkert et al., 2007; Wilder-Smith and Robert-Yap, 2007; Sutton et al., 200…”

“…et al., 1997; Ness et al., 2005; Powell-Boone et al., 2005) and vulvodynia/provoked vestibulodynia (Granot et al., 2002; Pukall et al., 2002, 2006; Giesecke et al., 2004; Foster et al., 2005; Granot, 2005; Granot and Lavee, 2005; Johannesson et al., 2007; Sutton et al., 2012; Hampson et al., 2013).”

“, 2013) and provoked vestibulodynia (Nunns and Mandal, 1997) are more likely to have anxiety or depression, but may otherwise be psychologically healthy (Eriksen et al.”

“…et al., 2010), IC (Clauw et al., 1997; Ness et al., 2005; Powell-Boone et al., 2005) and vulvodynia/provoked vestibulodynia (Granot et al., 2002; Pukall et al., 2002, 2006; Giesecke et al., 2004; Foster et al., 2005; Granot, 2005; Granot and Lavee, 2005; Johannesson et al., 2007; Sutton et al.,…”

“…ANS functioning (increased sympathetic and/or decreased parasympathetic activity) has been observed during sleep (Thompson et al., 2002), over a 24 h period (Heitkemperet al., 1998), and after stimulation of the sympathetic nervous system (Waring et al., 2004) when compared with healthy women.”

“…al., 1997; Granot et al., 2001; Bajaj et al., 2002; Vincent et al., 2011), endometriosis (Bajaj et al., 2003; Laursen et al., 2005; He et al., 2010; Neziri et al., 2010; As-Sanie et al., 2012), IBS (Wilder-Smith and Robert-Yap, 2007; Piche et al., 2010), IC (Clauw et al., 1997; Ness et al., 2005;…”

“In women with IBS, altered ANS functioning (increased sympathetic and/or decreased parasympathetic activity) has been observed during sleep (Thompson et al., 2002), over a 24 h period (Heitkemperet al., 1998), and after stimulation of the sympathetic nervous system (Waring et al., 2004) when…”

“have shown increased behavioural response to stimulation (both noxious and innocuous) of their bladder (Ness et al., 2005; Powell-Boone et al., 2005) and bowel (Song et al.”

“There are many methods available for generating a painful sensation including temperature change, application of pressure or electrical energy or distension of a hollow viscus.”

“However, these findings are not consistent, as not all studies observed an increase in all measures of the pain experience (Giamberardino et al., 1997; Bohm-Starke et al., 2001; Bajaj et al., 2002, 2003; Pukall et al., 2002; Songet al., 2006; Brinkert et al., 2007; Wilder-Smith and Robert-Yap, 2007; Sutton et al., 200…”

“…et al., 1997; Ness et al., 2005; Powell-Boone et al., 2005) and vulvodynia/provoked vestibulodynia (Granot et al., 2002; Pukall et al., 2002, 2006; Giesecke et al., 2004; Foster et al., 2005; Granot, 2005; Granot and Lavee, 2005; Johannesson et al., 2007; Sutton et al., 2012; Hampson et al., 2013).”

“…is of particular concern that many of the symptoms of CPP start in adolescence or early adult life (Zondervan et al., 1999a, b; Brosens et al., 2013), a time when the CNS is very plastic (Blakemore and Choudhury, 2006; Kalia, 2008) and thus potentially more vulnerable to repeated episodes of pain.”

“Moreover, it could underlie the frequently discussed, though not well proven (Raphael et al., 2004), link between abuse and chronic pain.”

“Similarly, the association of endometriosis with dyspareunia could be expected to increase psychological distress in these women (Meana et al., 1999).”

“This is true for conditions within the pelvis (e.g. IBS and IC/PBS (Rodriguez et al., 2009)) and at distant sites (e.g. CPP and migraine (Karp et al., 2011; Yang et al., 2012)).”

“Thus, abnormally lowcortisol levels havebeen observed in women with endometriosis and CPP (Petrelluzzi et al., 2008), dysmenorrhoea (Vincent et al., 2011) and provoked vulvodynia (Ehrstrom et al., 2009) and replicated over repeated measurements (Petrelluzzi et al., 2008; Vincent et al., 2011).”

“In fact, studies suggest that up to 50% of women have not received a diagnosis after many years follow-up (Grace, 1995; Zondervan et al., 1999a, b; Grace and Zondervan, 2004).”

“This is true for conditions within the pelvis (e.g. IBS and IC/PBS (Rodriguez et al., 2009)) and at distant sites (e.g. CPP and migraine (Karp et al., 2011; Yang et al., 2012)).”

“…et al., 1997; Ness et al., 2005; Powell-Boone et al., 2005) and vulvodynia/provoked vestibulodynia (Granot et al., 2002; Pukall et al., 2002, 2006; Giesecke et al., 2004; Foster et al., 2005; Granot, 2005; Granot and Lavee, 2005; Johannesson et al., 2007; Sutton et al., 2012; Hampson et al., 2013).”

“…that chronicpain can be consideredas a repeated stressor, both physiologically and psychologically, it is probably not surprising that dysfunction in the activity of the HPA axis is an almost universal finding in chronic pain conditions (Griep et al., 1998; Gaab et al., 2005; Galli et al., 2009).”

“Moreover, cortisol, as one of the principal players in the HPA axis, appears to be central to the phenomenon of stress-induced analgesia (Filaretov et al., 1996) and therefore a reduction in cortisol levels secondary to dysfunction of the HPA axis may exacerbate pain.”

“…et al., 1997; Ness et al., 2005; Powell-Boone et al., 2005) and vulvodynia/provoked vestibulodynia (Granot et al., 2002; Pukall et al., 2002, 2006; Giesecke et al., 2004; Foster et al., 2005; Granot, 2005; Granot and Lavee, 2005; Johannesson et al., 2007; Sutton et al., 2012; Hampson et al., 2013).”

“Chronic pelvic pain (CPP) is a major public health problem throughout the developed world (Mathias et al., 1996; Zondervan et al., 2001; Grace and Zondervan, 2004; Garcia-Perez et al., 2010).”

“, 2012) but is currently poorly investigated in CPP specifically (Sator-Katzenschlager et al., 2005; Horne et al., 2012).”

“A recent questionnaire study, assessed for the presence of autonomic symptoms (such as vasomotor symptoms, orthostatic intolerance and sleep disorder) in a small cohort of women with CPP (n ¼ 16) and pain-free controls (n ¼ 15) (Janicki et al., 2013).”

“A similar situation has been previously proposed to occur in rheumatoid arthritis (Straub and Cutolo, 2001).”

“46 47 Among endometriosis patients with central sensitization, the removal of the endometriotic lesions is unlikely to result in adequate pain remediation owing to continued activation of the central nervous system.”

“Similar to other chronic conditions, women with CPP (whether or not there was endometriosis present) had several volumetric modifications in specific brain areas (thalamus, insula, putamen, etc.) compared to pain-free women.”

“Neurogenic processes have been recently described in endometrium and endometriotic lesions contributing to explain the endometriosis-related pain mechanisms.(51,52) Local inflammatory, hormonal and angiogenetic mechanisms contribute to supporting neuronal growth.”

“The resulting pathologic changes involve the central nervous system’s response to noxious stimuli, the activation of specific brain regions, the hypothalamic–pituitary–adrenal axis, and the autonomic nervous system, all of which increase psychologic distress (16).”

“03), as well as clinical pain intensity (BPI, r(11)=0.”

“While a related review will focus on the central changes in endometriosis and pelvic pain (Brawn et al., 2014).”

“Reviewing the anatomical and biological causes of dyspareunia in endometriosis is beyond the scope of this review, and many other articles have extensively examined pain symptoms (Fauconnier and Chapron, 2005; Brawn et al., 2014; Morotti et al., 2014b).”

“Progestins and DNG have pronounced anti-inflammatory effects on the pelvic environment in women with endometriosis [27], we hypothesized that DNG might also act with other mechanism as a direct effect on the peripheral neuroinflammation [28,29] and thus to the central sensization mechanism, that are of paramount impor…”

“Inflammation is a major biological determinant in the pathogenesis of endometriosis,(13) and among the inflammatory mediators, a critical role is recognized to corticotropin-releasing hormone (CRH) and urocortin (Ucn),(14,15) whose expression in endometriotic lesions(16,17) has been correlated with stress and pain mec…”

“On the other hand, chronic pelvic pain in endometriosis is associated with central changes including alterations in the behavioral and central response to noxious stimulation that has the potential to both exacerbate symptoms and to predispose these women to the development of additional chronic conditions [28].”

“Finally, there are at least some data to suggest that there may be substantial differences in central pain processing among patients with chronic pain syndromes.(23) Patients with chronic pelvic pain have an increased behavioral response to noxious stimuli, both Table 1.”

“Once activated, ERK contributes to the induction and maintenance of a central and peripheral sensitization that also activates glial cells [150,159].”

“A purely physiologic approach to pain assumes that pain intensity relates to the degree of tissue damage, but this often cannot explain the wide range of reactions in humans in response to a painful stimulus (10, 20).”

“sleep deprivation, endocrine dysfunction and psychological distress) may also contribute to their experience of pain [12].”

“This phenomenon underscores the intricate nature of pain processing and perception in the CNS [130].”

“Neuropathic pain is associated with damage to the neurons themselves, following an infection or injury to the area, resulting in pain signals being sent to the central nervous system (CNS) regardless of noxious stimuli.(23) Neuropathic pain is often described as ‘‘shooting pain,’’ as it travels along the nerves in an…”

“While there are well-established relationships between the anatomical location of endometriotic lesions and pain (Fauconnier et al., 2002; Vercellini et al., 2007; Brawn et al., 2014; Morotti et al., 2014), the link between endometriosis and infertility is less well defined.”

“electrical energy) in women with CPP both with and without endometriosis (Bajaj et al., 2003; Brawn et al., 2014; Laursen et al., 2005) shows that, in both conditions, the experience of pain is deeply altered.”

“A purely physiological approach to pain assumes that pain intensity relates to the degree of tissue damage, but this often cannot explain the wide range of reactions in humans in response to a painful stimulus (Brawn et al., 2014; Sullivan et al., 2001).”

“At a population level, an estimated 2–11% of women of reproductive age has endometriosis [2, 3] often experiencing substantial burden of disease, including chronic pelvic pain and infertility [4, 5].”

“It has been suggested that people with chronic pain conditions have an impairment of endogenous inhibitory controls, which may be affected in part by genetic factors [125, 141].”

“In particular, Endometriosis appears to be deeply connected to sensitization and neuroplasticity mechanisms [9, 11], although neuropathic pain featuresmay occur in virtually anyCPP/CPPS patient [12, 13].”

“The women were not extensively evaluated for other comorbidities, such as endometriosis, that are common in this subpopulation and this might have led to other confounding biases [27,28].”

“Finally, dysregulation of pain perception is also believed to be common in endometriosis [54].”

“It can also be triggered by apparently innocuous stimuli such as touch (allodynia) and may even appear spontaneously with no obvious triggering factor or after an initial stimulus has disappeared or been eliminated such as following the clinical and/or surgical treatment of endometriosis.(25) One of the key events ass…”

“disproportionate to the extent of tissue damage.(8) Disruption of central regulatory systems essential to homeostasis, and associated with thermosensation and thermoregulation, can manifest as cold hypersensitivity (see Ref.”

““Central sensitization” manifests as hypersensitivity to pain occurring outside of the referred area of pain and has been implicated in various pelvic pain conditions, including CPP,(23) bladder pain,(24) irritable bowel syndrome,(25) and endometriosis.(23,26) Central sensitization is usually accompanied by allodynia…”

“It may also be due to the changes in pain perception that occur over time in people with endometriosis [28,29].”

“A third possibility is a central and peripheral hypersensitivity, as suggested by an increasing number of studies (27).”

“1,8,9 The endometriosis related changes may be due to plastic changes in the peripheral and central nervous system that possibly predispose for other long-lasting pain conditions, 3 therefore identifying pain alleviation strategies is of great importance.”

“21 Societal factors and poor awareness of endometriosis remain among the field’s most pertinent limitations, 6 facilitating the diagnostic delay through normalization .”

“…(e.g. endometriosis, adhesions), urological diseases (e.g. interstitial cystitis) or abdominal infections are often associated with CPP of somatic origin which is in many cases the leading symptom of these diseases (Ortiz, 2008; Vercellini et al., 2009; Vincent, 2009; Brawn et al., 2014).”

“Whilst there is relatively limited research on this in the context of chronic pelvic pain, studies that have looked at these features confirm similarities with other chronic pain conditions such as irritable bowel syndrome (IBS), rheumatoid arthritis and fibromyalgia (11, 12).”

“Women with endometriosis frequently experience symptoms of dysmenorrhea, dyspareunia and chronic fatigue (2), and it may interfere with the functioning of their bowel or bladder, depending on the site where endometriotic lesions develop (3); up to 50% experience infertility (4).”

“Endometriosis is a definite peripheral nociceptive trigger and may often be the initiating event; however, there is an evolving body of knowledge supporting PPP as manifestation of central sensitisation (4-6).”

“Selecting a homogeneous patient sample with regard to the disease history is important because previous research has shown diseasespecific brain morphological alterations, for example, in patients with migraines (Hubbard et al., 2014) and chronic pelvic pain (Brawn et al., 2014).”

“Early detection would be of value to avoid sensitization and development of chronic pelvic pain (2, 3).”

“…diseases such as Parkinson’s disease, autoimmune disorders such as rheumatoid arthritis, and other conditions such as cancers and endometriosis all experience pain symptoms [3–6]. ability to accurately recognise the occurrence of pain in a clinical setting is therefore crucial to help patients.”